The present invention relates to a genus of substituted oximes useful as antagonists of tachykinin receptors, in particular as antagonists of the neuropeptides neurokinin-1 receptor (NK.sub.1) and/or neurokinin-2 receptor (NK.sub.2) and/or neurokinin-3 receptor (NK.sub.3).
Neurokinin receptors are found in the nervous system and the circulatory system and peripheral tissues of mammals, and therefore are involved in a variety of biological processes. Neurokinin receptor antagonists are consequently expected to be useful in the treatment or prevention of various mammalian disease states, for example asthma, cough, chronic obstructive pulmonary disease (COPD), bronchospasm, emesis, neurodegenerative disease, ocular disease, inflammatory diseases such as arthritis, central nervous system conditions such as migraine and epilepsy, nociception, psychosis and various gastrointestinal disorders such as Crohn's disease.
In particular, NK.sub.1 receptors have been reported to be involved in microvascular leakage and mucus secretion, and NK.sub.2 receptors have been associated with smooth muscle contraction, making NK.sub.1 and NK.sub.2 receptor antagonists especially useful in the treatment and prevention of asthma.
Some NK.sub.1 and NK.sub.2 receptor antagonists have previously been disclosed: arylalkylamines were disclosed in U.S. Pat. No. 5,350,852, issued Sep. 27, 1994, and spirosubstituted azacycles were disclosed in WO 94/29309, published Dec. 22, 1994.
U.S. Pat. No. 5,696,267 discloses compounds represented by the generic structure ##STR3## or a pharmaceutically acceptable salt thereof, wherein: a is 0, 1,2 or 3;
R is H, C.sub.1-6 alkyl, --OH or C.sub.2 --C.sub.6 hydroxyalkyl; PA1 b, d and e are independently 0, 1 or 2; PA1 T is H, phthalimidyl, aryl, heterocycloalkyl, heteroaryl, cycloalkyl or bridged cycloalkyl; PA1 Q is --SR.sup.6, --N(R.sup.6)(R.sup.7), --OR.sup.6, phenyl, naphthyl or heteroaryl; PA1 R.sup.6a, R.sup.7a, R.sup.8a, R.sup.9a, R.sup.6 and R.sup.7 are H, C.sub.1-6 alkyl, C.sub.2 --C.sub.6 hydroxyalkyl, C.sub.1 --C.sub.6 alkoxy-C.sub.1 --C.sub.6 alkyl, phenyl or benzyl; or R.sup.6 and R.sup.7, together with the nitrogen to which they are attached, form a ring; PA1 R.sup.9a is R.sup.6 or --OR.sup.6 ; PA1 R.sup.1 is H, methyl, ethyl, --CH.sub.2 CN, --CH.sub.2 C(O)NH.sub.2, --(CH.sub.2).sub.3 SO.sub.3 H, --CH.sub.2 C(O)NHCH.sub.3, --CH.sub.2 C(O)NHOH, --CH.sub.2 C(O)NHOCH.sub.3, --CH.sub.2 C(O)NHCH.sub.2 CN, --CH.sub.2 F, --CH.sub.2 C(O)NHCH.sub.2 SO.sub.3 H, ##STR6## R.sup.2 is 2-3 substituents independently selected from the group consisting of chloro, methyl and methoxy; PA1 R.sup.3 is 2 to 3 substituents independently selected from the group consisting of chloro and methyl; PA1 R.sup.4 is methyl or ethyl; and PA1 Z is ##STR7##
A is an optionally substituted oxime, hydrazone or olefin;
X is a bond, --C(O)--, --O--, --NR.sup.6 --, --S(O).sub.e --, --N(R.sup.6)C(O)--, --C(O)N(R.sup.6)-- --OC(O)NR.sup.6 --, --OC(.dbd.S)NR.sup.6 --, --N(R.sup.6)C(.dbd.S)O--, --C(.dbd.NOR.sup.1)--, --S(O).sub.2 N(R.sup.6)--, --N(R.sup.6)S(O).sub.2 --, --N(R.sup.6)C(O)O--or --OC(O)--;
Z is morpholinyl, optionally N-substituted piperazinyl, optionally ##STR4## g is 0-3 and h is 1-4, provided the sum of h and g is 1-7; wherein aryl, heterocycloalkyl, heteroaryl, cycloalkyl and bridged cycloalkyl groups are optionally substituted.
We have found that certain compounds within that generic structure show surprisingly greater activity as neurokinin antagonists than those previously specifically disclosed.